# NM_001083614.2(EARS2):c.1287A>T (p.Ala429=)

https://sugi.bio/variant/ears2-p-ala429

## Summary

**EARS2 p.Ala429= (c.1287A>T)** is classified **Uncertain significance** in EARS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). Very rare (popmax 0.00644%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs374785094 · 1 submitter · very rare (popmax 0.00644%, nfe)

## For patients & families {#patients}

This is a change in the EARS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EARS2](https://sugi.bio/atlas/gene/EARS2/) |
| Protein change (HGVS p.) | p.Ala429= |
| Coding change (HGVS c.) | c.1287A>T |
| MANE Select transcript | [NM_001083614](https://www.ncbi.nlm.nih.gov/nuccore/NM_001083614) |
| dbSNP | [rs374785094](https://www.ncbi.nlm.nih.gov/snp/rs374785094/) |
| Variant type | single nucleotide variant |
| Location | chr16:23529567-23529567 (GRCh38) |
| ClinVar | [VCV2179920](https://www.ncbi.nlm.nih.gov/clinvar/variation/2179920/) |

**All HGVS expressions:** `NC_000016.10:g.23529567T>A`, `NC_000016.9:g.23540888T>A`, `NG_027752.2:g.32809A>T`, `NM_001083614.2:c.1287A>T`, `NM_001308211.1:c.1287A>T`, `NM_133451.1:c.1287A>T`, `NR_003501.2:n.1294A>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.67) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -8.877, GERP -3.69 — fast-evolving / accelerated position
- CADD: **PHRED 11.22**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.14**, donor loss **0.00**, acceptor gain **0.67**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.67**, donor gain **0.00**.
- Pangolin: Δ**0.40** (gain), gain 0.40 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00644%** (nfe) · FAF95 0.00527% · FAF99 0.00482% · 76/1,180,032 in the highest group · 77/1,614,042 alleles overall — very rare (popmax 0.00644%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00644% | 15,527 |
| South Asian | 0.0011% | 91,072 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**EARS2** population constraint: LOEUF 1.138, pLI 7.0535e-14, missense-Z 0.080959; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Leigh syndrome** — Definitive (AR)
- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.84, 79% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of EARS2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** EARS2's established molecular role includes glutamate-tRNA ligase activity.


### Pathways affected {#pathways}

EARS2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial tRNA aminoacylation](https://reactome.org/content/detail/R-HSA-379726) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** glutamate-tRNA ligase activity, glutamate-tRNA(Gln) ligase activity.

**Biological process:** glutamyl-tRNA aminoacylation, tRNA aminoacylation for mitochondrial protein translation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-25.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-25 |

**Reported phenotype names (ClinVar):** not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM.

## Similar variants {#similar}

Related EARS2 variant pages (same residue, condition, or type): [EARS2 p.Arg107His](/variant/ears2-p-arg107his), [EARS2 p.Arg108Trp](/variant/ears2-p-arg108trp), [EARS2 p.Cys167Tyr](/variant/ears2-p-cys167tyr), [EARS2 p.Gly317Cys](/variant/ears2-p-gly317cys), [EARS2 p.Met1Val](/variant/ears2-p-met1val), [EARS2 p.Ser143Ter](/variant/ears2-p-ser143ter), [EARS2 p.Ala263Thr](/variant/ears2-p-ala263thr), [EARS2 p.Ala299Val](/variant/ears2-p-ala299val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2179920). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*